The neuronal storage disorders are inherited defects in specific lysosomal hydrolases and are characterized by profound neurobehavioral deterioration and death. Although significant progress has been made in determining the specific enzymatic defects responsible for individual diseases, little is understood as to the ways in which resulting metabolic derrangements precipitate altered brain function. The discovery that storage disorders are characterized by neuron type-specific ectopic dendrite growth and new synapse formation, occurring well after the usual phase of dendritogenesis in normal nervous systems, has opened a new chapter in the study of these disorders. Fully understanding the causes and consequences of these alterations in neuronal connectivity may offer important clues to those factors underlying the process of synapse development and maintenance in normal nervous systems. Pursuant of this understanding, a series of experiments designed to explore two central hypotheses on the pathobiology of neuronal storage disease will be carried out. These hypotheses relate to (i) the source(s), functional consequence(s), and modifiability of the observed, altered synaptic connectivity, and (ii) the possible role of gangliosides in the induction of ectopic neurite (i.e., dendrite) growth. Immunocytochemical studies directed at specific neurotransmitters and a lectin-based anterograde transport method, in combination with Golgi staining and EM, will be employed to evaluate three specific, hypothesized changes in neuronal connectivity within cerebral cortex. These concern the intrinsic GABAergic system, and the intracortical distribution of cholinergic and thalamocortical afferents. Biochemical analyses and immunocytochemical studies with anti-ganglioside antibodies will be used to explore the hypothesized role of gangliosides in inducing ectopic neuritogenesis. A key element in these studies will be the availability of well characterized, biologically equivalent diseases in animals. The present study makes use of several inherited models of the gangliosidoses and of alpha- mannosidosis, and to a remarkable phenocopy of the latter as induced (reversibly) by a plant-derived alpha-mannosidase inhibitor (swainsonine). Taken as a whole, these studies can be expected to generate important new data on the phenomena of ectopic dendrite growth and new synapse formation in neuronal storage disorders, and to better relate these changes to events in the normal nervous system.